Chronic exposure to mercury, a highly reactive heavy metal, may increase cardiovascular disease (CVD) risk. Because the major environmental exposure to mercury is from fish intake, which may otherwise have significant cardiovascular benefits, and because adequate data are critical to ongoing policy decisions regarding mercury contaminants, elucidating the relationship between mercury and CVD risk is of great scientific and public health importance. However, results of prior studies have been inconsistent, and prior studies excluded women and did not evaluate stroke, a major cause of CVD morbidity and mortality. Selenium, an essential dietary trace element, plays an important role in antioxidant defense systems and may protect against both CVD and toxic effects of mercury. Such a protective effect would have direct implications for recommendations regarding optimal selenium intake and for assessing the potential impact of mercury contamination from fish intake in selenium-replete populations. However, the possible interaction between mercury, selenium, and cardiovascular risk is not well-established. The objectives of this application are to assess the associations between mercury and selenium exposure and risk of coronary heart disease (CHD) and stroke in women and men. It is hypothesized that: 1. Chronic mercury exposure is associated with higher risk of CVD (CHD and stroke) in women and men. 2. Selenium intake is associated with lower risk of CVD. 3. The relation between mercury levels and CVD risk varies depending on intake of selenium. These aims will be investigated using a prospective nested case-control design among women and men participating in two large U.S. cohort studies, including 6,470 incident CVD cases. Exposures will be ascertained using stored toenail clippings, a reliable biomarker of chronic mercury and selenium intake. This study provides a unique and cost-efficient opportunity to evaluate the importance of mercury and selenium intake for cardiovascular risk in women and men. This research will greatly clarify the potential risks and benefits offish intake, mercury exposure, and selenium intake for cardiovascular disease prevention, fulfilling the NIH's mission to pursue fundamental knowledge about human health and illness and the application of that knowledge to extend healthy life and reduce burdens of death and disability.